Yuval Shaked

Technion - Israel Institute of Technology, H̱efa, Haifa, Israel

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Publications (102)739.55 Total impact

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    ABSTRACT: The c-Jun Dimerization Protein 2, JDP2, is a basic leucine zipper protein member of the activator protein-1 (AP-1) family of transcription factors. JDP2 typically suppresses gene transcription through multiple mechanisms and plays a dual role in multiple cellular processes, including cell differentiation and proliferation which is dependent on AP-1 function. Whereas the role of JDP2 expression within cancer cells has been studied, its role in stromal cells at the tumor microenvironment is largely unknown. Here we show that mice lacking JDP2 (JDP2-/-) display a reduced rate of metastasis in Lewis lung carcinoma (LLC) and polyoma middle T-antigen (PyMT) breast carcinoma mouse models. The replacement of wild-type bone marrow derived cells (BMDCs) with JDP2-deficient BMDCs recapitulates the metastatic phenotype of JDP2-/- tumor-bearing mice. In vitro, conditioned medium of wild-type BMDCs significantly potentiates the migration and invasion capacity of LLC cells as compared to that of JDP2-/- BMDCs. Furthermore, wild-type BMDCs secrete CCL5, a chemokine known to contribute to metastasis, to a greater extent than JDP2-/- BMDCs. The supplementation of CCL5 in JDP2-/- BMDC conditioned medium was sufficient to potentiate the invasion capacity of LLC. Overall, this study suggests that JDP2-expressing BMDCs within the tumor microenvironment contribute to metastatic spread.
    No preview · Article · Oct 2015 · Oncotarget
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    ABSTRACT: A major therapeutic obstacle in clinical oncology is intrinsic or acquired resistance to therapy, leading to subsequent relapse. We have previously shown that systemic administration of different cytotoxic drugs can induce a host response that contributes to tumor angiogenesis, regrowth and metastasis. Here we characterize the host response to a single dose of local radiation, and its contribution to tumor progression and metastasis. We show that plasma from locally irradiated mice increases the migratory and invasive properties of colon carcinoma cells. Furthermore, locally irradiated mice intravenously injected with CT26 colon carcinoma cells succumb to pulmonary metastasis earlier than their respective controls. Consequently, orthotopically implanted SW480 human colon carcinoma cells in mice that underwent radiation, exhibited increased metastasis to the lungs and liver compared to their control tumors. The irradiated tumors exhibited an increase in the colonization of macrophages compared to their respective controls; and macrophage depletion in irradiated tumor-bearing mice reduces the number of metastatic lesions. Finally, the anti-tumor agent, dequalinium-14, in addition to its anti-tumor effect, reduces macrophage motility, inhibits macrophage infiltration of irradiated tumors and reduces the extent of metastasis in locally irradiated mice. Overall, this study demonstrates the adverse effects of local radiation on the host that result in macrophage-induced metastasis.
    Full-text · Article · Sep 2015 · Oncotarget
  • Lilach Koren · Yuval Shaked · Ami Aronheim

    No preview · Article · Aug 2015 · International journal of cardiology
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    ABSTRACT: Pressure overload induces adaptive remodeling processes in the heart. However, when pressure overload persists, adaptive changes turn into maladaptive alterations leading to cardiac hypertrophy and heart failure. ATF3 is a stress inducible transcription factor that is transiently expressed following neuroendocrine stimulation. However, its role in chronic pressure overload dependent cardiac hypertrophy is currently unknown. The objective of the study was to study the role of ATF3 in chronic pressure overload dependent cardiac remodeling processes. Pressure overload was induced by phenylephrine (PE) mini-osmotic pumps in various mice models of whole body, cardiac specific, bone marrow (BM) specific and macrophage specific ATF3 ablations. We show that ATF3-KO mice exhibit a significantly reduced expression of cardiac remodeling markers following chronic pressure overload. Consistently, the lack of ATF3 specifically in either cardiomyocytes or BM derived cells blunts the hypertrophic response to PE infusion. A unique cross-talk between cardiomyocytes and macrophages was identified. Cardiomyocytes induce an ATF3 dependent induction of an inflammatory response leading to macrophage recruitment to the heart. Adoptive transfer of wild type macrophages, but not ATF3-KO derived macrophages, into wild type mice potentiates maladaptive response to PE infusion. Collectively, this study places ATF3 as a key regulator in promoting pressure overload induced cardiac hypertrophy through a cross-talk between cardiomyocytes and macrophages. Inhibiting this cross-talk may serve as a useful approach to blunt maladaptive remodeling processes in the heart. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
    No preview · Article · Jul 2015 · International journal of cardiology

  • No preview · Article · May 2015
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    ABSTRACT: Acquired resistance to therapy is a major obstacle in clinical oncology, and little is known about the contributing mechanisms of the host response to therapy. Here we show that the pro-inflammatory cytokine, IL-1β, is overexpressed in response to paclitaxel chemotherapy in macrophages, subsequently promoting the invasive properties of malignant cells. In accordance, blocking IL-1β, or its receptor, using either genetic or pharmacologic approach, results in slightly retardation of primary tumor growth; however, it accelerates metastasis spread. Tumors from mice treated with combined therapy of paclitaxel and the IL-1 receptor antagonist, Anakinra, exhibit increased number of M2 macrophages and vessel leakiness when compared to paclitaxel monotherapy treated mice, indicating a pro-metastatic role of M2 macrophages in the IL-1β-deprived microenvironment. Taken together, these findings demonstrate the dual effects of blocking the IL-1 pathway on tumor growth. Accordingly, treatments using 'add-on' drugs to conventional therapy should be investigated in appropriate tumor models consisting of primary tumors and their metastases. Copyright © 2015, American Association for Cancer Research.
    No preview · Article · Apr 2015 · Molecular Cancer Therapeutics
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    ABSTRACT: Unbiased proteomic analysis of plasma samples holds the promise to reveal clinically invaluable disease biomarkers. However the tremendous dynamic range of the plasma proteome has so far hampered the identification of such low abundant markers. To overcome this challenge we analyzed the plasma microparticle proteome, and reached an unprecedented depth of over 3,000 plasma proteins in single runs. To add a quantitative dimension, we developed PROMIS-Quan PROteomics of MIcroparticles with Super-SILAC Quantification, a novel mass spectrometry-based technology for plasma microparticle proteome quantification. PROMIS-Quan enables a two step relative and absolute SILAC quantification. First, plasma microparticle proteomes are quantified relative to a super-SILAC mix composed of cell lines from distinct origins. Next, the absolute amounts of selected proteins of interest are quantified relative to the super-SILAC mix. We applied PROMIS-Quan to prostate cancer and compared plasma microparticle samples of healthy individuals and prostate cancer patients. We identified in total 5,374 plasma-microparticle proteins, and revealed a predictive signature of 3 proteins that were elevated in the patient-derived plasma microparticles. Finally, PROMIS-Quan enabled determination of the absolute quantitative changes in prostate specific antigen (PSA) upon treatment. We propose PROMIS-Quan as an innovative platform for biomarker discovery, validation and quantification in both the biomedical and in the clinical worlds. Copyright © 2015, The American Society for Biochemistry and Molecular Biology.
    No preview · Article · Jan 2015 · Molecular & Cellular Proteomics
  • Ofrat Beyar Katz · Yuval Shaked
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    ABSTRACT: There are several approaches for the management of malignant disease. However, tumor resistance to therapy is still a major challenge in the clinic. Efflux transporters, genetic responses and enzyme activity in tumor cells are examples of the main modalities that account for resistance to therapy. In addition, emerging evidence suggests that the host also plays a significant role in promoting therapy resistance. Recruitment of different host cell types to the treated tumor site occurs in response to a range of therapies, including chemotherapy, radiation, surgery and even targeted drugs. This host response may have a protective effect on the tumor cells, not only negating anti-tumor activity, but also promoting a resistant tumor. In this review we focus on host-tumor interactions leading to therapy resistance with special emphasis on different host cells and secreted factors within the tumor microenvironment. The development of novel inhibitors that block the host response to therapy could be used as a treatment strategy to enhance therapy outcomes and survival.
    No preview · Article · Dec 2014 · Drug Resistance Updates
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    ABSTRACT: The Fourth Metronomic and Anti-angiogenic Therapy Meeting was held in Milan 24-25 June 2014. The meeting was a true translational meeting where researchers and clinicians shared their results, experiences, and insights in order to continue gathering useful evidence on metronomic approaches. Several speakers emphasised that exact mechanisms of action, best timing, and optimal dosage are still not well understood and that the field would learn a lot from ancillary studies performed during the clinical trials of metronomic chemotherapies. From the pre-clinical side, new research findings indicate additional possible mechanisms of actions of metronomic schedule on the immune and blood vessel compartments of the tumour micro-environment. New clinical results of metronomic chemotherapy were presented in particular in paediatric cancers [especially neuroblastoma and central nervous system (CNS) tumours], in angiosarcoma (together with beta-blockers), in hepatocellular carcinoma, in prostate cancer, and in breast cancer. The use of repurposed drugs such as metformin, celecoxib, or valproic acid in the metronomic regimen was reported and highlighted the potential of other candidate drugs to be repurposed. The clinical experiences from low- and middle-income countries with affordable regimens gave very encouraging results which will allow more patients to be effectively treated in economies where new drugs are not accessible. Looking at the impact of metronomic approaches that have been shown to be effective, it was admitted that those approaches were rarely used in clinical practice, in part because of the absence of commercial interest for companies. However, performing well-designed clinical trials of metronomic and repurposing approaches demonstrating substantial improvement, especially in populations with the greatest unmet needs, may be an easier solution than addressing the financial issue. Metronomics should always be seen as a chance to come up with new innovative affordable approaches and not as a cheap rescue strategy.
    Full-text · Article · Sep 2014 · ecancermedicalscience
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    ABSTRACT: Acute chemotherapy can induce rapid bone-marrow derived pro-angiogenic cell (BMDC) mobilization and tumor homing, contributing to tumor regrowth. In order to study the contribution of tumor cells to tumor regrowth following therapy, we focused on tumor-derived microparticles (TMPs). EMT/6 murine-mammary carcinoma cells exposed to paclitaxel chemotherapy exhibited an increased number of TMPs and significantly altered their angiogenic properties. Similarly, breast cancer patients had increased levels of plasma MUC-1+TMPs following chemotherapy. In addition, TMPs from cells exposed to paclitaxel induced higher BMDC mobilization and colonization but had no increased effect on angiogenesis in Matrigel plugs and tumors than TMPs from untreated cells. Since TMPs abundantly express osteopontin, a protein known to participate in BMDC trafficking, the impact of osteopontin-depleted TMPs on BMDC mobilization, colonization, and tumor angiogenesis was examined. While EMT/6 tumors grown in mice inoculated with osteopontin-depleted TMPs had lower numbers of BMDC infiltration and microvessel density compared with EMT/6 tumors grown in mice inoculated with wild-type TMPs, no significant difference in tumor growth was seen between the two groups. However, when BMDCs from paclitaxel-treated mice were injected into wild-type EMT/6-bearing mice, a substantial increase in tumor growth and BMDC infiltration was detected compared to osteopontin-depleted EMT/6-bearing mice injected with BMDCs from paclitaxel-treated mice. Collectively, our results suggest that osteopontin expressed by TMPs play an important role in BMDC mobilization and colonization of tumors, but is not sufficient to enhance the angiogenic activity of BMDCs in tumors. © 2013 Wiley Periodicals, Inc.
    No preview · Article · Jul 2014 · International Journal of Cancer
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    ABSTRACT: Metronomic, low dose chemotherapy may have anti-angiogenic effects and augment the effects of lenalidomide in MDS and CMML. We evaluated the clinical efficacy, tolerability and anti-angiogenic effects of melphalan 2 mg and lenalidomide 10 mg for 21 days/28 in CMML (n = 12) and higher risk MDS (n = 8) patients in a prospective phase II study. The primary endpoint was overall response and secondary endpoints included survival, progression-free survival toxicity and biomarkers of angiogenesis. The median age was 73 years, 55% were pretreated and transfusion dependent. The overall response rate was 3(15%) of 19 evaluable patients but 25% in CMML and 33% in pCMML. Dose reductions and/or delays occurred were common due to myelosuppression. Transient spikes in circulating endothelial cells that declined below baseline were seen in responders and patients with CMML, suggesting anti-angiogenic activity. Conclusions: Lenalidomide and metronomic low dose melphalan demonstrate signals of clinical and possible anti-angiogenic activity in patients with pCMML that require future validation. This trial was registered at clinicaltrial.gov under # NCT00744536.
    Preview · Article · Jul 2014 · Leukemia research
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    ABSTRACT: Weekly gemcitabine therapy is the major treatment offered for patients with pancreatic adenocarcinoma cancer; however, relative resistance of tumor cells to chemotherapy, rapid regrowth, and metastasis are the main causes of death within a year. Recently, the daily continuous administration of chemotherapy in low doses - called metronomic chemotherapy (MC) - has been shown to inhibit primary tumor growth and delay metastases in several tumor types; however, its use as a single therapy is still in question due to its moderate therapeutic benefit. Here, we show that the combination of weekly gemcitabine with MC of the same drug delays tumor regrowth and inhibits metastasis in mice implanted orthotopically with pancreatic tumors. We further demonstrate that weekly gemcitabine, but not continuous MC gemcitabine or the combination of the two drug regimens, promotes rebound myeloid-derived suppressor cell (MDSC) mobilization and increases angiogenesis in this tumor model. Furthermore, Bv8 is highly expressed in MDSCs colonizing pancreatic tumors in mice treated with weekly gemcitabine compared to MC gemcitabine or the combination of the two regimens. Blocking Bv8 with antibodies in weekly gemcitabine-treated mice results in a significant reduction in tumor regrowth, angiogenesis, and metastasis. Overall, our results suggest that pro-tumorigenic effects induced by weekly gemcitabine are mediated in part by MDSCs expressing Bv8. Therefore, both Bv8 inhibition and MC can be used as legitimate 'add-on' treatments for preventing post-chemotherapy pancreatic cancer recurrence, progression, and metastasis following weekly gemcitabine therapy.
    Preview · Article · Jun 2014 · Neoplasia (New York, N.Y.)

  • No preview · Article · May 2014 · Cancer Research
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    ABSTRACT: Tumor derived microparticles (TMPs) have recently been shown to contribute to tumor re-growth partially by inducing the mobilization and tumor homing of specific bone marrow derived pro-angiogenic cells (BMDCs). Since antiangiogenic drugs block proangiogenic BMDC mobilization and tumor homing, we asked whether TMPs from cells exposed to an antiangiogenic drug may affect BMDC activity and trafficking. Here we show that the level of VEGF-A is reduced in TMPs from EMT/6 breast carcinoma cells exposed to the anti-VEGF-A antibody, B20. Consequently, these TMPs exhibit reduced angiogenic potential as evaluated by a Matrigel plug and Boyden chamber assays. Consistently, BMDC mobilization, tumor angiogenesis, microvessel density and BMDC-colonization in growing tumors are reduced in mice inoculated with TMPs from B20-exposed cells as compared to mice inoculated with control TMPs. Collectively, our results suggest that the neutralization of VEGF-A in cultured tumor cells can block TMP-induced BMDC mobilization and colonization of tumors and hence provide another mechanism of action by which antiangiogenic drugs act to inhibit tumor growth and angiogenesis.
    Full-text · Article · Apr 2014 · PLoS ONE
  • Tali Voloshin · Ella Fremder · Yuval Shaked
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    ABSTRACT: A wide spectrum of both normal and diseased cell types shed extracellular vesicles that facilitate intercellular communication without direct cell-to-cell contact. Microparticles (MPs) are a subtype of extracellular vesicles that participate in multiple biological processes. They carry abundant bioactive molecules including different forms of nucleic acids and proteins that can markedly modulate cellular behavior. MPs are involved in several hallmarks of cancer such as drug resistance, thrombosis, immune evasion, angiogenesis, tumor invasion and metastasis. Such MPs originate from either cancer or other host cells. As MPs are secreted and can be detected in various body fluids, they can be used as potential diagnostic and prognostic biomarkers as well as vehicles for delivery of cytotoxic drugs. This review summarizes accumulating evidence on the biological properties of MPs in cancer, with reference to their potential usage in clinical settings.
    No preview · Article · Apr 2014 · Cancer Microenvironment
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    ABSTRACT: Weekly gemcitabine therapy is the major treatment offered for patients with pancreatic adenocarcinoma cancer; however, relative resistance of tumor cells to chemotherapy, rapid regrowth, and metastasis are the main causes of death within a year. Recently, the daily continuous administration of chemotherapy in low doses – called metronomic chemotherapy (MC) – has been shown to inhibit primary tumor growth and delay metastases in several tumor types; however, its use as a single therapy is still in question due to its moderate therapeutic benefit. Here, we show that the combination of weekly gemcitabine with MC of the same drug delays tumor regrowth and inhibits metastasis in mice implanted orthotopically with pancreatic tumors. We further demonstrate that weekly gemcitabine, but not continuous MC gemcitabine or the combination of the two drug regimens, promotes rebound myeloid-derived suppressor cell (MDSC) mobilization and increases angiogenesis in this tumor model. Furthermore, Bv8 is highly expressed in MDSCs colonizing pancreatic tumors in mice treated with weekly gemcitabine compared to MC gemcitabine or the combination of the two regimens. Blocking Bv8 with antibodies in weekly gemcitabine-treated mice results in a significant reduction in tumor regrowth, angiogenesis, and metastasis. Overall, our results suggest that pro-tumorigenic effects induced by weekly gemcitabine are mediated in part by MDSCs expressing Bv8. Therefore, both Bv8 inhibition and MC can be used as legitimate 'add-on' treatments for preventing post-chemotherapy pancreatic cancer recurrence, progression, and metastasis following weekly gemcitabine therapy.
    Preview · Article · Jan 2014
  • Yuval Shaked · Sandra McAllister · Ofer Fainaru · Nava Almog
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    ABSTRACT: Although escape from tumor dormancy has long been recognized as an important problem in the treatment of cancer, the molecular and cellular regulators underlying this transition remain poorly understood. The inability of the cancer cells to induce a complete and successful process of angiogenesis can result in tumor dormancy. In this case, the acquisition of sufficient angiogenic potential will result in the escape from indolence and in the initiation of tumor mass expansion. This stage in disease progression is known as the angiogenic switch. It is now becoming clear that the induction of the angiogenic switch is controlled by dynamic and complex biological processes involving the cancer cells, the associated stromal microenvironment and distant normal host cells, mostly from the bone marrow. Indeed, intricate tumor-host interactions are increasingly recognized as critical features of cancer. In particular, infiltrating cells of the immune system are crucial constituents of tumors and an important source of the growth stimulatory signals to the tumor cells. Tumor cells are surrounded by stromal cells, such as fibroblasts, lymphocytes, neutrophils, macrophages and mast cells, which communicate via a complex network of intercellular signaling pathways, mediated by surface adhesion molecules, cytokines and their receptors. However, the possible roles of these cells and molecules in the maintenance of micro-tumors in an occult state and in the induction of exit from the dormant state are not fully elucidated. In this review, we summarize recent findings and the current understanding of the role of bone marrow-derived cells, their recruitment into tumors and their interactive crosstalk with tumor cells, in leading to either the maintenance of, or exit from, tumor dormancy. Understanding the mechanisms of tumor growth and metastatic recurrence after periods of indolence is crucial for improving early detection, as well as increasing the cure rate for cancer patients.
    No preview · Article · Nov 2013 · Current pharmaceutical design
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    ABSTRACT: We previously reported that the host response to certain chemotherapies can induce primary tumor regrowth, angiogenesis, and even metastases in mice, but the possible impact of anti-vascular endothelial growth factor-A (VEGF-A) therapy in this context has not been fully explored. We therefore used combinations of anti-VEGF-A with chemotherapy on various tumor models in mice including primary tumors, experimental lung metastases, and spontaneous lung metastases of 4T1-breast and CT26-colon murine cancer cell lines. Our results show that a combined treatment with anti-VEGF-A and folinic acid/5-fluorouracil/oxaliplatin (FOLFOX) but not with anti-VEGF-A and gemcitabine/cisplatinum (Gem/CDDP) enhances the treatment outcome partly due to reduced angiogenesis, in both primary tumors and in experimental lung metastases models. However, neither treatment group exhibited an improved treatment outcome in the spontaneous lung metastases model nor were changes in endothelial cell numbers found at metastatic sites. Since chemotherapy has recently been shown to induce tumor cell invasion, we tested the invasion properties of tumor cells when exposed to plasma from FOLFOX-treated mice or cancer patients. While plasma from FOLFOX-treated mice or patients induced invasion properties of tumor cells, the combination of anti-VEGF-A and FOLFOX abrogated these effects, despite the reduced plasma VEGF-A levels detected in FOLFOX-treated mice. These results suggest that the therapeutic impact of antiangiogenic drugs varies in different tumor models, and that anti-VEGF-A therapy can block the invasion properties of tumor cells in response to chemotherapy. These results may implicate an additional therapeutic role for anti-VEGF-A when combined with chemotherapy.
    Preview · Article · Oct 2013 · Molecular Cancer Therapeutics

  • No preview · Article · Aug 2013 · Cancer Research
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    ABSTRACT: Lysyl oxidase-like 2 (LOXL2), a secreted enzyme that catalyzes the cross-linking of collagen, plays an essential role in developmental angiogenesis. We found that administration of the LOXL2 neutralizing antibody AB0023 inhibited bFGF-induced angiogenesis in Matrigel plug assays and suppressed recruitment of angiogenesis promoting bone marrow cells. ShRNA-mediated inhibition of LOXL2 expression or inhibition of LOXL2 using AB0023 reduced the migration and network forming ability of endothelial cells suggesting that the inhibition of angiogenesis results from a direct effect on endothelial cells. To examine the effects of AB0023 on tumour angiogenesis, AB0023 was administered to mice bearing tumours derived from SKOV-3 ovarian carcinoma or Lewis lung carcinoma (LLC) cells. AB0023 treatment significantly reduced the microvascular density in these tumours, but did not inhibit tumour growth. However, treatment of mice bearing SKOV-3-derived tumours with AB0023 also promoted increased coverage of tumour vessels with pericytes and reduced tumour hypoxia, providing evidence that anti-LOXL2 therapy results in the normalization of tumour blood vessels. In agreement with these data, treatment of mice bearing LLC-derived tumours with AB0023 improved the perfusion of the tumour-associated vessels as determined by ultra-sonography. Improved perfusion and normalization of tumour vessels after treatment with anti-angiogenic agents was previously found to improve the delivery of chemotherapeutic agents into tumours, and to result in an enhancement of chemotherapeutic efficiency. Indeed, treatment with AB0023 significantly enhanced the anti-tumourigenic effects of taxol. Our results suggest that inhibition of LOXL2 may prove beneficial for the treatment of angiogenic tumours.
    Preview · Article · Jul 2013 · Carcinogenesis

Publication Stats

5k Citations
739.55 Total Impact Points

Institutions

  • 2009-2015
    • Technion - Israel Institute of Technology
      H̱efa, Haifa, Israel
  • 2003-2011
    • University of Toronto
      • • Department of Medical Biophysics
      • • Department of Medicine
      Toronto, Ontario, Canada
  • 2005-2008
    • Sunnybrook Health Sciences Centre
      • Division of Molecular and Cell Biology
      Toronto, Ontario, Canada